Airway Epithelial Cell Biology - Stem Cells, Host Defense & Response to Injury
Research in the Randell lab is currently focused on four areas where a greater knowledge of basic cell biology can be applied towards overcoming clinical lung disease problems.
Identification of airway epithelial stem cells. The airway epithelium occupies a critical interface between organism and environment and its normal physiologic function is essential for host well-being. It is central to the pathogenesis of asthma, chronic bronchitis, cystic fibrosis, well known and emerging infectious diseases, lung cancer, post transplant lung allograft rejection, and is a prime target for gene therapy. Understanding basic cellular processes such as progenitor-progeny relationships and regulation of proliferation and differentiation is of fundamental importance. However, stem cells of this tissue and patterns of cell renewal and migration, at steady state, after injury, or in disease, have not yet been identified with certainty. Our goals are to identify and isolate airway epithelial stem cells and to understand molecular mechanisms regulating airway epithelial cell proliferation and fate decisions.
Micro RNA Regulation of Human Airway Epithelial Phenotype- ARRA Award.
Greater than 30 million people in the USA suffer from respiratory diseases characterized by airway inflammation and obstruction. Cells lining the airway respond to injury and are integral to the progression of lung disease. However, many basic mechanisms regulating their function remain poorly understood. There are no specific therapies directed at treating disease related changes in the airway epithelium. Micro RNAs (miRNAs) are a class of small RNA molecules known to regulate many aspects of cell behavior. Together with Drs. Scott Hammond in Cell and Developmental Biology and D. Neil Hayes in Medicine, the Randell Lab was awarded an ARRA RC1 Challenge grant to comprehensively determine the miRNA repertoire of human airway epithelial cells and to test the ability of miRNAs to alter cell structure and function. These studies will create a valuable database and will suggest novel treatments for lung disease.
Innate immunity in the airway. The airway epithelium is poised to detect and respond to noxious stimuli. It can act either as a “sensor” or “insulator”, thereby determining the intensity of the inflammatory response. While vital for eliminating pathogens penetrating initial physical barriers, airway inflammation is a two-edged sword that must be precisely regulated. Thus, for every pro-inflammatory event, anti-inflammatory mechanisms are induced to return the host to homeostasis. Adaptation to the continuous presence of pathogens must be very important in chronic infectious airway diseases such as cystic fibrosis and chronic bronchitis, but remains understudied and poorly understood. We have found that airway epithelial cells become partially tolerant to the respiratory tract pathogen Pseudomonas aeruginosa at the mRNA level but that inflammatory cytokine protein production is sustained, which may explain severe inflammation in chronic infectious airway diseases. Our goals are to better understand molecular mechanisms regulating airway epithelial adaptation to injury and chronic infection and to understand the relationship of adaptation to the pathogenesis of airway disease.
Post-lung transplant ischemia reperfusion injury and bronchiolitis obliterans syndrome. Lung transplantation is a final option for many patients with end stage lung disease. However due to a limited supply of transplantable lungs, many individuals die on the waiting list. The extensive surgery entails an approximately 15% one-year mortality rate and lung transplants fare the worst of all solid organs, with only 50% 5 year survival. I feel a strong obligation towards improving the outcome of lung transplantation. Studies of lung ischemia reperfusion injury may help to develop strategies to enhance the supply of transplantable lungs and to lengthen storage time to allow for histocompatibility matching. We are also examining basic mechanisms of airway epithelial injury in the allogenic environment to better understand bronchiolitis obliterans syndrome, the leading cause of lung allograft failure.
The UNC CF Center Tissue Procurement and Cell Culture Core (S. Randell, Director) provides primary and passaged human airway and alveolar epithelial cells, lung microvascular endothelial cells, media and expertise to CF Center investigators and collaborators. We support novel models of relevance to the research mission of several UNC investigators and have recently produced superior cell lines as better tools for research and development. Our facility has become a nationally and internationally recognized resource whose services are sought for collaboration, contract research, and training by academics, non-profit organizations, biotech and the pharmaceutical industry.